The present invention relates to a process for preparing 2,4,5,6-tetraaminopyrimidine sulfate. More particularly, it relates to a process for preparing 2,4,5,6-tetraaminopyrimidine sulfate, represented by formula (I), by reducing 5-nitroso-2,4,6-triaminopyrimidine, represented by formula (II), with zinc in the presence of a suitable acid to the corresponding acid salt of 2,4,5,6-tetraaminopyrimidine, and converting the latter to the sulfate salt. The product (I) is useful as an intermediate in the synthesis of methotrexate, an antineoplastic agent for treating cancer in humans. ##STR1##
The reduction of 5-nitroso-2,4,6-triaminopyrimidine, hereafter referred to as NTAP, with sodium dithionite and treatment of the resulting 2,4,5,6-tetraaminopyrimidine with sulfuric acid, to form the desired compound of formula (I), hereafter referred to as TAPS, is well known in the art. See, e.g., J. Chem. Soc., 3721 (1953), discussed more fully below. However, the use of sodium dithionite results in the formation of undesirable sulfamate impurities which cannot be easily removed by conventional methods such as reslurrying or recrystallization. The level of impurity may be as high as 40-area percent, as determined by high-pressure liquid chromatography. There is a need, therefore, for a process for the reduction of NTAP to give a reaction mixture which upon acidification with sulfuric acid will give TAPS in high yields and without the sulfamate impurity.
The Applicants are not aware of any prior art publication which, in their respective judgment as a person skilled in the art of preparing 2,4,5,6-tetraaminopyrimidine sulfate, anticipates or renders obvious the process of this invention. However, to fully develop the background of this invention and to establish the state of the requisite art, the following publications are set forth:
U.S. Pat. No. 2,473,802 discloses the preparation of 2,4,5-triamino-6-hydroxypyrimidine by the reduction of 2,4-diamino-5-nitroso-6-hydroxypyrimidine with a mixture of zinc dust and ammonium hydroxide;
Netherlands Patent Application No. 7,712,155, published Jan. 23, 1979, discloses the preparation of 2,4,5,6-tetraaminopyrimidine by the reduction of 5-nitroso-2,4,6-triaminopyrimidine with Raney nickel, or with a nickel salt and sodium borohydride, in an aqueous suspension;
J. Chem. Soc., 3721 (1953), discloses the reduction of several 5-nitrosopyrimidines using sodium dithionite, and the precipitation of the product as an insoluble sulfate salt. Among the compounds prepared in this manner are 6-hydroxy-2,4,5-triaminopyrimidine sulfate and 4,5-diamino-2,6-dihydroxypyrimidine sulfate;
J.A.C.S. 69, 1814 (1947), discloses the preparation of 2,4,5,6-tetraaminopyrimidine bisulfite by reacting 5-nitroso-2,4,6-triaminopyrimidine with sodium dithionite in water at a temperature of about 60.degree.-70.degree. C. The yield of the product obtained was 54% of theoretical;
J.A.C.S. 55, 1667 (1933), discloses the use of sodium dithionite to reduce the 5-nitroso-6-aminouracil to 5,6-diaminouracil. The 5,6-diaminouracil is then isolated as the sulfate salt; and
Berichte 37, 4544 (1904), discloses the preparation of 2,4,5,6-tetraaminopyrimidine sulfate by the reduction of 5-nitroso-2,4,6-triaminopyrimidine with ammonium sulfide.
The process of the present invention has the following advantages:
1. The real yield is increased to about 82.5-88.5% versus less than 75% for the dithionite process.
2. The purity of the product is increased to about 99.5% versus about 60-90% for the product of the dithionite process.
3. Productivity is increased about 30% over the dithionite process because the reduction can be carried out at higher concentrations.
4. The need for careful temperature control and pH control is eliminated.
5. The zinc reducing agent is noncorrosive and is easily removed from the effluent liquors thus avoiding discharging of zinc in the effluent.
6. The discharge of sulfurous by-product emissions from dithionite in the reactor and effluent is avoided.
In accordance with the present invention, a process for preparing 2,4,5,6-tetraaminopyrimidine sulfate (TAPS) comprises (1) reacting about one molecular proportion of 5-nitroso-2,4,6-triaminopyrimidine (NTAP) in water with about 2.0 to 2.5 molecular proportions of zinc dust and about 4.0 to 4.7 molecular proportions of a suitable acid, to provide a reaction mixture having a pH below 7; (2) reacting the reaction mixture at a temperature of about 20.degree. to 65.degree. C. to form the acid salt of 2,4,5,6-tetraaminopyrimidine; (3) adjusting the pH to about 2.0 to 2.5 by adding the suitable acid to form a solution of the acid salt; (4) separating the insoluble materials from step (3) to obtain a wet cake and a mother liquor; (5) adding sulfuric acid to the mother liquor to adjust the pH to about 0.2 to 0.5 while maintaining the temperature at about 20.degree. to 60.degree. C.; (6) cooling the reaction mixture of step (5) to about 0.degree. to 10.degree. C. to precipitate 2,4,5,6-tetraaminopyrimidine sulfate; and (7) recovering the precipitate.
In one embodiment, in step (1) the zinc dust is added to provide an initial mixture having a pH of about 8 to 10 and then the suitable acid is added at a rate to provide a temperature rise of about 1.degree. C. per minute and a final pH of about 5 to 6. In a preferred embodiment, in step (1) about 2.1 to 2.2 molecular proportion of zinc dust are added and then about 4.1 to 4.2 molecular proportions of hydrochloric acid are added, to provide a final temperature of about 50.degree. to 65.degree. C. and a final pH of about 5.5 to 5.7; in step (3) the pH is adjusted to about 2.2 to 2.4; and in step (5) about 15-20% by weight of sulfuric acid is added to adjust the pH to about 0.2 to 0.5 while maintaining the temperature at about 40.degree. to 45.degree. C. In a most preferred embodiment, the hydrochloric acid is a mixture of one part by volume of concentrated hydrochloric acid and one part by volume of water.
In another embodiment, in step (1) the zinc dust and acid are added concurrently at a rate to provide a temperature rise of about 1.degree. C. per minute and a final pH of about 5 to 6. In a preferred embodiment, in step (1) about 2.1 to 2.2 molecular proportions of zinc dust and about 4.1 to 4.2 molecular proportions of hydrochloric acid per molecular proportion of 5-nitroso-2,4,6-triaminopyrimidine are added concurrently at a rate to provide a final temperature of about 50.degree. to 65.degree. C. and a final pH of about 5.5 to 5.7; in step (3) the pH is adjusted to about 2.2 to 2.4; and in step (5) about 15-20% by weight of sulfuric acid is added to adjust the pH to about 0.2 to 0.5 while maintaining the temperature at about 40.degree. to 45.degree. C. In a most preferred embodiment, the hydrochloric acid is a mixture of one part by volume of concentrated hydrochloric acid and one part by volume of water.
In yet another embodiment, the acid is selected from the group consisting of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, formic acid, acetic acid, and mixtures thereof.